Download evaluation of antidepressant like activity of curcumin and its

Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 68 No. 5 pp. 769ñ775, 2011
ISSN 0001-6837
Polish Pharmaceutical Society
EVALUATION OF ANTIDEPRESSANT LIKE ACTIVITY OF CURCUMIN
AND ITS COMBINATION WITH FLUOXETINE AND IMIPRAMINE:
AN ACUTE AND CHRONIC STUDY
JAYESH SANMUKHANI, ASHISH ANOVADIYA and CHANDRABHANU B. TRIPATHI*
Department of Pharmacology, Government Medical College, Bhavnagar ñ 364001, Gujarat, India
Abstract: Curcumin is the active ingredient of commonly used spice Curcuma longa Linn. In the present study,
the antidepressant like activity of curcumin and its combination with fluoxetine and imipramine was studied in
acute model (three doses 24, 5 and 1 h before test) of forced swimming test (FST) in glass jar and tail suspension test (TST) in mice and in chronic model (14 day study) of FST with water wheel in rats. All the tests were
carried out in the following seven groups (n = 6 in each group), drugs being given orally (doses for mice):
Group 1 (vehicle), group 2 (curcumin 50 mg/kg), group 3 (curcumin 100 mg/kg), group 4 (fluoxetine 20
mg/kg), group 5 (imipramine 15 mg/kg), group 6 (curcumin 100 mg/kg plus fluoxetine 20 mg/kg) and group 7
(curcumin 100 mg/kg plus imipramine 15 mg/kg). Equivalent doses for rats were used. Both the acute model
of FST and TST, and the chronic model of FST with water wheel showed significant antidepressant like activity of curcumin in 100 mg/kg dose as compared to vehicle control (p < 0.05). The effect of curcumin (100
mg/kg) was similar to that of fluoxetine and imipramine (p > 0.05) but its addition to fluoxetine and imipramine
did not improve their antidepressant activity (p > 0.05). Curcumin increased both the swimming and climbing
behavior in FST, thus its antidepressant like activity could be due to an increase in serotonin, norepinephrine
and dopamine levels in the brain. Curcumin can be a useful antidepressant especially in cases which respond to
drugs having mixed effects on serotonin and catecholamines levels in the brain.
Keywords: curcumin, antidepressant, forced swimming test (FST), tail suspension test (TST)
most commonly used but have a lot of distressing
adverse effects as they are often used for very long
period of time. Moreover, most of the patients
respond to a single drug (most commonly a SSRI or
a TCA) but only about 30% achieve remission
(complete normalization of symptoms), thus, combination therapy of antidepressants with different
mechanism of action or those having mixed effects
on serotonin (5HT) and catecholamines i.e., norepinephrine (NE) and dopamine (DA) levels in brain
are often required (4). This also adds up to the
adverse effects of individual drugs. Therefore,
search for antidepressants with broader spectrum of
action and a benign profile of adverse effects continues.
Extract of rhizomes of Curcuma longa Linn.
has been used to treat mental disorders in the past. It
is a major constituent of Xiaoyao-san and Jieyuwan, the traditional Chinese herbal medicines,
which have been effectively used to manage stress
and depression related disorders in China (5).
Curcumin is the active principle in this extract of
Depression is a mental illness characterized by
profound and persistent feeling of sadness or despair
and/or loss of interest in things that were once
pleasurable. The life time risk of depression varies
from 5% to 12% in men and 10% to 25% in women
(1). It is responsible for the largest proportion of disease burden attributable to non-fatal health outcomes, accounting for almost 12% of total years
lived with disability worldwide (2). Patients with
depression have decreased social, occupational, and
educational functioning. Moreover, they have high
medical morbidity and are often plagued with more
pain and physical illness than the general population. It has been estimated that 15% of patients with
severe depressive episodes commit suicide. An
accurate diagnosis followed by effective treatment
can improve this outcome (3).
Depression shows a good response to pharmacological and behavioral treatments, individually or
in combination. Among the various pharmacological agents selective serotonin reuptake inhibitors
(SSRIs) and tricyclic antidepressants (TCAs) are
* Corresponding author: e-mail: [email protected]; mobile: +919825951678
769
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JAYESH SANMUKHANI et al.
rhizomes of Curcuma longa Linn. It is known to
have antioxidant, anti-inflammatory, immunodulatory, anticancer and neuroprotective properties
(6ñ9). Though there have been some reports of antidepressant like action of curcumin, its effect as add
on to commonly prescribed antidepressants via oral
route has not been studied. The route of administration of curcumin holds special importance as
bioavailability of curcumin via oral route is quite
low.
This work was planned to assess the antidepressant like activity of curcumin in two different
doses and to see its effect as an add on therapy to the
two most commonly prescribed antidepressants in
our setting, fluoxetine and imipramine, via oral
route in acute and chronic models in two different
animal species.
MATERIALS AND METHODS
Drugs
Curcumin not less than (NLT) 95% (Bio-curcuminÆ, Arjuna Natural Extracts Ltd., Alwaye,
Kerala, India); fluoxetine hydrochloride (Cadila
Pharmaceuticals Ltd., Gujarat, India) and
imipramine hydrochloride (Sun Pharmaceutical
Industries Ltd., Mumbai, India); gum acacia
Figure 1. Chemical structure of curcumin, fluoxetine and imipramine
(Fischer Scientific, Mumbai, India) were used in the
study (Fig. 1). Curcumin suspension was made in
5% gum acacia, which was used as vehicle control.
Fluoxetine hydrochloride and imipramine
hydrochloride were dissolved in distilled water.
Dose of curcumin was calculated by using data
from ancient Chinese medicine. They used dry rhizome of Curcuma longa Linn. in a dose of 3ñ9 g/70
kg adult for treating depressive disorders (5).
Considering a median dose of 6 g/70 kg and curcumin content of dry rhizomes to be about 5ñ6%
(10), dose of curcumin NLT 95% comes out to be 50
mg/kg in mice using surface area ratios (11).
Therefore, curcumin was tested in a dose of 50
mg/kg and 100 mg/kg in mice and equivalent doses
used for rats were 35 mg/kg and 70 mg/kg.
Fluoxetine hydrochloride was used in a dose of
20 mg/kg in mice; equivalent dose for rats was calculated (14 mg/kg) using surface area ratios (11).
Imipramine hydrochloride was used in dose of 15
mg/kg in mice and 10.5 mg/kg in rats (12).
Animals
Swiss albino mice threeñfour months of age
(26 to 34 g) and albino rats of Wistar strain (160 to
220 g) of either sex were procured from the central
animal house of the institute. They were housed in
Evaluation of antidepressant like activity of curcumin and its combination...
standard polypropylene cages and kept under controlled room temperature (24 ± 2OC) in a 12 h lightdark cycle. The animals were given standard laboratory diet and water ad libitum. The animals were
acclimatized to the laboratory conditions at least one
day prior to the behavioral experiments. All the
experiments were carried out between 12:00 to
16:00 h. Food was withdrawn 12 h before the experiments. Each animal was used only once. The animal handling was performed according to the Good
Laboratory Practice (GLP) guidelines. All the
experiments were performed after the prior permission from the Institutional Animal Ethics Committee
(IAEC), Government Medical College, Bhavnagar
(Gujarat, India).
Study design
The antidepressant like activity of curcumin
and its combination with fluoxetine and imipramine
was evaluated by forced swimming test (FST) in
glass jar and tail suspension test (TST) after acute
(three doses) dosing in mice; and forced swimming
test with activity wheel after chronic (14 days) dosing in rats. Locomotor activity was also tested after
acute dosing in mice. All the tests were done in
seven groups of animals with at least six animals in
each group.
Acute study
The groups for acute dose study in mice were
as follows: Group 1 (vehicle control group): 5%
gum acacia (2.5 mL/kg) 24, 5 and 1 h orally before
the test. Group 2 (curcumin 50 mg/kg): curcumin
suspension in a dose of 50 mg/kg orally 24, 5 and 1
h orally before the test. Group 3 (curcumin 100
mg/kg): curcumin suspension in a dose of 100
mg/kg orally 24, 5 and 1 h orally before the test.
Group 4 (fluoxetine): fluoxetine hydrochloride in a
dose of 20 mg/kg orally 24, 5 and 1 h orally before
the test. Group 5 (imipramine): imipramine
hydrochloride in a dose of 15 mg/kg orally 24, 5 and
1 h orally before the test. Group 6 (curcumin plus
fluoxetine): fluoxetine hydrochloride in a dose of 20
mg/kg and curcumin suspension in a dose of 100
mg/kg orally 24, 5 and 1 h orally before the test.
Group 7 (curcumin plus imipramine): imipramine
hydrochloride in a dose of 15 mg/kg and curcumin
suspension in a dose of 100 mg/kg orally 24, 5 and
1 h orally before the test.
Chronic study
The protocol for drug administration in chronic study in rats was the same as that in acute study
except that the drugs were given for fourteen days,
771
last dose being given 1 h before the test and equivalent doses for rats as calculated by surface area
ratios were used.
Forced swimming test in glass jar
FST in glass jar was performed as described by
Porsolt et al. with few modifications (13). This test
consists of two parts, an initial training period of 15
min followed by actual test for 5 min duration 24 h
later. Mice were individually forced to swim inside
a vertical borosilicate glass cylinder (height: 40 cm;
diameter: 15 cm; containing 15 cm hight of water
maintained at 25 ± 1OC). Mice placed in the cylinder
for the first time were initially highly active, vigorously swimming in circles, trying to climb the wall
or diving to the bottom. After 2ñ3 min, activity
began to subside and was interspersed with phases
of immobility or floating of increasing length. After
5ñ6 min, immobility reached a plateau where the
mice remained immobile for approximately 80% of
the time. After 15 min in the water, the mice were
removed, wiped with dry cloth and allowed to dry
before being returned to their home cages. The
cylinders were emptied and washed thoroughly after
testing for each mouse. The mice were again placed
in the cylinder 24 h later after three doses of drug
and their activity was recorded from above for 5 min
using a digital camera The recordings were later
analyzed by a rater who was blinded to the treatment
condition, to find the duration of immobility, swimming behavior and climbing behavior in the 5 min
test period using stopwatch. An animal was judged
to be immobile whenever it remained floating passively in the water in a slightly hunched but upright
position, its nose just above the surface, with no
additional activity other than that necessary to keep
its head above water. Swimming was defined as
active movement throughout the swim chamber,
which included crossing into another quadrant.
Climbing activity (also termed thrashing) consisted
of upward directed movements of the forepaws
along the side of the swim chamber.
Tail suspension test
TST was done as described by Steru et al. (14).
After three doses of drugs, mice were suspended on
a string held by a metal stand, by an adhesive tape
placed 1 cm from the tip of the tail. This string was
58 cm above the table top. The activity of the mice
was recorded using a digital camera for a period of
5 min. During the experiment, each animal under
test was both acoustically and visually isolated from
other animals. The videos were analyzed by a rater
blinded for treatment condition to find the duration
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JAYESH SANMUKHANI et al.
Table 1. Effect of drugs on immobility, swimming and climbing time in forced swimming test in mice in acute study.
Treatment group
Dose
(mg/kg)
per os
Immobility
time (s)
(mean ± SEM)
Swimming
time (s)
(mean ± SEM)
Climbing
time (s)
(mean ± SEM)
Vehicle control
2.5 mL/kg
40.0 ± 5.5
35.3 ± 11.8
Fluoxetine
20
224.7 ± 13.8
110.7 ± 16.5*
Imipramine
15
127.3 ± 15.9*
144.5 ± 11.1*
41.8 ± 5.3
45.8 ± 9.4
Curcumin 50 mg/kg
50
173.5 ± 18.4
126.8 ± 10.8*
67.7 ± 10.7#^
Curcumin 100 mg/kg
100
90.0 ± 13.7#
143.8 ± 10.5*
98.3 ± 16.0*#
63.5 ± 10.9
56.2 ± 9.7
Fluoxetine plus curcumin
20 + 100
111.7 ± 8.6*
76.5 ± 22.0*
mipramine plus curcumin
15 + 100
113.5 ± 15.1*
123.0 ± 19.2*
F
9.27
10.77
3.55
One way ANOVA
dF
6,35
6,35
6,35
p
< 0.0001
< 0.0001
0.007
79.7 ± 16.6
Statistical analysis of data was carried by one-way ANOVA followed by Tuckey-Kramer multiple comparisons test. *p < 0.05 as compared to vehicle control; #p < 0.05 as compared to fluoxetine; ^p < 0.05 as compared to imipramine; n = 6 in each group.
Table 2. Effect of drugs on immobility time in tail suspension test and total counts of locomotor activity in photoactometer in mice in acute
study.
Treatment group
Dose (mg/kg)
per os
Immobility time (s)
(mean ± SEM)
Total counts
(mean ± SEM)
Vehicle control
2.5 mL/kg
157.8 ± 17.9
115.7 ± 11.1
Fluoxetine
20
40.7 ± 13.0*
116.8 ± 22.1
Imipramine
15
64.5 ± 23.4*
105.8 ± 13.5
Curcumin 50 mg/kg
50
72.8 ± 14.5*
119.3 ± 16.4
Curcumin 100 mg/kg
100
69.7 ± 21.7*
114.5 ± 14.2
Fluoxetine plus curcumin
20 + 100
42.5 ± 14.1*
120.5 ± 11.0
Imipramine plus curcumin
15 + 100
84.7 ± 5.2
140.3 ± 25.5
F
5.6
0.381
One way ANOVA
dF
p
6,35
< 0.001
6,36
0.886
Statistical analysis of data was carried by one-way ANOVA followed by Tuckey-Kramer multiple comparisons test. * p < 0.05 as compared to control; n = 6 in each group.
Table 3. Effect of drugs on number of counts in forced swimming test with activity wheel in rats in chronic study
Treatment group
Dose (mg/kg)
per os
No. of rotations
(mean ± SEM)
Vehicle control
5 mL/kg
Fluoxetine
14
Imipramine
10.5
17.7 ± 1.1
42.5 ± 1.3*
49.5 ± 2.6*
Curcumin 35 mg/kg
35
Curcumin 70 mg/kg
70
Fluoxetine plus curcumin
14 + 70
Imipramine plus curcumin
10.5 + 70
37.2 ± 2.7*
46.7 ± 1.7*
42.0 ± 5.4*
46.6 ± 2.0*
Statistical analysis of data was carried by one-way ANOVA followed by Tuckey-Kramer multiple comparisons test. F
(6,35 ) = 15.1 (p < 0.0001). * p < 0.05 as compared to control; n = 6 in each group.
Evaluation of antidepressant like activity of curcumin and its combination...
of immobility in seconds. Mice were considered
immobile when they hang passively and completely
motionless.
Forced swimming test (FST) with activity wheel
The FST with activity wheel was first
described by Nomura et al. (15) and is based on
despair swim paradigm described by Porsolt et al.
One hour after the last dose of fourteen day treatment of rats, they were forced to swim in an apparatus consisting of a water tank (30 ◊ 20 ◊ 15 cm) with
a water wheel (25 cm diameter) in its centre. The
tank was filled with water up to a height of 13 cm
maintained at 25 ± 1OC. When placed in the tank,
rats tried to escape from the tank but ended up in
rotating the wheel. The number of times the wheel
was rotated by rats in a 5 min test period, as recorded in the digital counter of the instrument, was
noted. The tank was cleaned after experiment with
each rat.
Measurement of locomotor activity
The locomotor activity of animals was measured to differentiate between sedative and central
nervous system stimulant activity of drugs. It was
measured by using a digital photo actometer
(Teknik, India). After three doses of drugs 24, 5 and
1 h before the test, mice were placed in the photo
actometer covered with the fibre lid. Mice tried to
explore the area and during their movement they
intercepted the photobeams. The number of interceptions was counted by the photoactive cells.
Locomotion of the animal was expressed in terms of
total number of ambulations (total photobeam
counts) during a 5-min test for each mouse.
Statistical analysis
All the results are expressed as the mean ±
standard error (SEM). Data were analyzed using
one-way analysis of variance (ANOVA), followed
by Tukey-Kramer multiple comparisons test to
determine statistical significance of various groups
as compared to vehicle, fluoxetine and imipramine
groups. Statistical significance was set at p < 0.05.
All the analyses were done using SPSS Statistics
(17.0).
RESULTS
In the acute model of FST in glass jar with
mice (Table 1) all the test groups, except curcumin
in a dose of 50 mg/kg, showed a significant decrease
in immobility time as compared to the vehicle control group (p < 0.05). There was a trend towards
773
decreasing the immobility time with increasing dose
of curcumin. The effect of 100 mg/kg curcumin was
similar to that of fluoxetine and imipramine.
Combination of curcumin in a dose of 100 mg/kg
further decreased the immobility time of fluoxetine
and imipramine, but the decrease was not statistically significant. The swimming time in fluoxetine,
imipramine, fluoxetine plus curcumin and
imipramine plus curcumin groups was significantly
higher as compared to the vehicle control (p < 0.05),
while that in curcumin (100 mg/kg) group, though
not statistically significant, was more than twice
than that in the vehicle control. The climbing time
significantly increased only in curcumin 100 mg/kg
group as compared to vehicle control (p < 0.05).
In the TST model in mice (Table 2) there was
a significant decrease in immobility time in all the
groups as compared to vehicle control (p < 0.05)
except in imipramine plus curcumin group. The
antiimmobility effect of curcumin was comparable
to that of fluoxetine and imipramine (p > 0.05).
Combination of curcumin and imipramine nonsignificantly increased the immobility time of mice
as compared to imipramine alone (p > 0.05).
In the chronic study model of FST in rats
(Table 3), the study groups affected the number of
rotations significantly [F (6,35 ) = 15.1 (p <
0.0001)]. All the drugs showed a significant increase
in the number of rotations as compared to vehicle (p
< 0.05) but neither curcumin, nor its combination
with fluoxetine or imipramine showed statistically
significant difference as compared to fluoxetine or
imipramine alone (p > 0.05).
Locomotor activity of mice (Table 2), as measured using digital photo actometer, was found to be
similar in all the groups [F (6,35) = 0.381 (p =
0.886)].
DISCUSSION
The present study showed that curcumin has
antidepressant like activity similar to that of fluoxetine and imipramine in both acute and chronic models but fails to significantly improve the activity of
fluoxetine and imipramine when added to them.
The findings that curcumin (active ingredient
of Curcuma longa Linn.) significantly decreases the
time of immobility in FST and TST and increases
the number of rotations in FST with water wheel as
compared to vehicle control are in accordance with
previous reports with crude aqueous extract of
Curcuma longa Linn. (16). The study showed that
curcumin does not improve the antiimmobility
effect of fluoxetine and imipramine when given per
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JAYESH SANMUKHANI et al.
os whereas in an earlier study Kulkarni SK et al.
(17) it was shown that curcumin, when given by
intraperitoneal route, significantly increased the
antiimmobility effect of subthreshold dose of fluoxetine (5 mg/kg) but not of imipramine (5 mg/kg).
The difference in findings could be due to use of
subtherapeutic dose in the previous study, while full
recommended dose of fluoxetine was used in the
present study. Another reason for the different
observation could be a pharmacokinetic interaction
of curcumin with fluoxetine and imipramine. In the
present study both the drugs were administered
together via oral route, while the previous study
used the drugs via intraperitoneal route.
The distinction in the swimming and the climbing behaviors helped in prediction of the possible
neurotransmitters involved in the antidepressant like
action of curcumin. Curcumin in a dose of 100
mg/kg increased both the swimming and the climbing behaviors in mice. It has been previously suggested by RÈnÈric and Lucki (18) that an increase in
both swimming and climbing behaviors in the FST
occurs when the animal is treated by a drug which
increases serotonin, norepinephrine and dopamine
levels in the nerve terminals. An increase in all the
three neurotransmitters could be by inhibition of
monoamine oxidase (MAO) activity in the brain.
These findings are supported by other studies showing inhibition of MAO activity by curcumin and
involvement of serotonergic and dopaminergic system in its antidepressant like activity (17, 19, 20).
A growing body of research indicates that
besides depletion of serotonin and catechoamine
neurotransmitters, depression could result from various other pathophysiological mechanisms as well.
Researchers suggest that depression may inhibit
neurogenesis in the hippocampus (21). This idea is
supported by the finding that antidepressants can
promote neurogenesis (22). Curcumin administration has also shown to increase hippocampal neurogenesis in chronically stressed rats; this could be via
modulation of hypothalamic-pituitary-adrenal
(HPA) axis and up regulation of 5-HT1A receptors
and the brain derived neurotrophic factor (BDNF) in
the hippocampus (9). This mechanism may also
underlie the therapeutic actions of curcumin during
chronic treatment. Activation of innate immunity
via nuclear factor-κB (NF-κB) and mitogen activated protein kinases has also been implicated in the
pathophysiology of depression. NF-κB leads to
increased release of interferon-α and other
cytokines, which eventually lead to dysregulation of
HPA axis, metabolism of monoamine neurotrans-
mitters and neuronal plasticity (23). Curcumin
inhibits the NF-κB activation pathways and thus can
help in treatment of depression by interfering at an
early stage in its pathogenesis (24).
The battery of tests applied in two different
species of animals has minimized the false positive
and false negative results in this study. Rats are
more selective (fewer false positives) while mice are
more sensitive (fewer false negatives) for screening
new antidepressants (25). The modified FST with
water wheel gives an objective approach and helps
to remove observational errors. As increasing of
diameter of glass jar in FST decreases, the more
false are positive results (26); using a diameter of 15
cm, larger than one used by Porsolt et al. (10 cm),
reduces the false positive results. The results of photoactometer showed that curcumin did not increase
the locomotor activity as compared to vehicle control, fluoxetine and imipramine, thus showing that
the antidepressant like effect was not due to central
nervous stimulation.
The most important hindrance in the use of
curcumin is its low bioavailability via oral route.
The curcumin formulation (Bio-curcuminÆ) used in
this study had other curcuminoids and volatile oils
added to it, increasing its retention and bioavailability by seven times (27).
Curcumin can be an antidepressant of choice
especially in cases which respond to drugs having
mixed effects on serotonin and catecholamines levels in the brain (28). Previously, reversible inhibitors
of monoamine oxidase were used in such cases but
their use has declined due to their adverse effects
and life threatening interactions. Curcumin might be
useful in such cases, as it increases the serotonin,
norepinephrine and dopamine levels in the brain.
Moreover, it has been proved to be safe and devoid
of adverse effects even in high doses of up to 8 g/day
taken for several weeks in human studies (29).
CONCLUSION
This study shows that curcumin in the doses of
50 mg/kg and 100 mg/kg in mice; and 35 mg/kg and
70 mg/kg in rats has antidepressant like action, similar to that of fluoxetine and imipramine; however, it
does not increase the antidepressant action of fluoxetine and imipramine when administered by oral
route. Curcumin may be developed as an antidepressant but might not be useful in combination with
fluoxetine and imipramine. Further research is
required to gain closer insights into the exact mechanism of its action.
Evaluation of antidepressant like activity of curcumin and its combination...
Acknowledgments
The authors are thankful to Mr. Binu T
Kuruvilla, Arjuna Natural Extracts Ltd., Alwaye,
Kerala, India for providing curcumin powder and
Dr. Shravanti Bhowmik, Medical Adviser, Sun
Pharmaceuticals Pvt. Ltd, Mumbai, India for providing fluoxetine and imipramine pure powder for
this work. The authors are also grateful to Dr. J.C.
Sanmukhani, Head of Department of Medicine,
Pushpa Mission Hospital, Ujjain, Madhya Pradesh
for critical review of this manuscript.
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Received: 22. 09. 2010